Inflammation a Potential Target for Therapeutic Intervention in Heart Failure

The concept of chronic heart failure (CHF) has evolved over time from just a simple "pump-failure" to a more complex syndrome involving the activation of different compensatory mechanisms. Activation of the immune system, for example, can result in the production and release of proinflammatory cytokines, production of antibodies, and activation of the complement system.

Several conditions contribute to the development of CHF. Initially, the heart is exposed to a primary insult such as myocardial infarction (Ml), hypertension, viral infection or toxins (e.g., ethanol). The subsequent loss of myocardium, due to all compensatory mechanisms, creates a localized or generalized muscle dysfunction. Finally, the myocardium becomes more defective and weaker, producing symptoms typical of CHF.

The immune activation is part of the pathophysiology of heart failure. It can be divided into two broad categories: 1) immune activation secondary to cardiac injury, and 2) immune activation by direct antigenic stimulation. In the first category, new antigenic peptides are present in the myocardium and have the capacity to induce an immune response. Two common examples are the presence of numerous inflammatory cells at the area of infarction after an acute Ml, and antibodies against myosin found in patients with idiopathic dilated cardiomyopathy (IDCM) (Figure 1 ). The second category is characterized by two clinical scenarios: acute cardiac allograft rejection and acute myocarditis. The myocardium of a heart transplant recipient undergoing rejection is infiltrated by mononuclear cells, B and T lymphocytes that are capable of producing cytokines and cardiac dysfunction. In patients with acute myocarditis, the cardiotrophic virus infects the cardiac cell and triggers multiple immune mechanisms involving mononuclear, T and B cells, in turn producing inflammatory cytokines such as tumor necrosis factor-alpha (TNF-a) and interleukin (IL)-6 and releasing free radicals that affect cardiac function. Clinically, both conditions characteristically produce revers1ble myocardial dysfunction, and biopsy findings from both pathologies may be indistinguishable. Therefore, inflammation plays a significant contributory role in the pathogenesis of CHF.

Many studies have shown increased plasma levels of pro,nflammatory cytokines (i.e., TNF-a and IL-6) in patients with CHF. Normal myocardium does not contain TNF-a; however, as myocardial function starts failing, TNF-o: receptors of type I and II over-express in the myocardium.¹ In addition, increasing evidence suggests that both T and B cells are actively involved in CHF. Our group at the Methodist DeBakey Heart & Vascular Center studied the role of B-cell activation during acute exacerbations of heart failure 1n patients with CHF and found a threefold increase in CD69 expression that returned to normal by six weeks, which may be related to a preferential activation of B cells but not T cells during acute heart failure decompensation.2

Chronic heart failure is clearly a complex syndrome, and immune activation plays an important role in the initiation and further perpetuation of myocardial dysfunction.